Non-steroidal progesterone receptor modulators

ABSTRACT

The present invention relates to non-steroidal progesterone receptor modulators of the general formula I,  
                 
a process for their preparation, the use of the progesterone receptor modulators for producing medicaments, and pharmaceutical compositions comprising these compounds. The compounds according to the invention are suitable for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea, and for the therapy and prophylaxis of hormone-dependent tumours and for use for female fertility control and for hormone replacement therapy.

This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/693,403 filed Jun. 24, 2005.

The present invention relates to non-steroidal progesterone receptor modulators, to a process for their preparation, to the use of the progesterone receptor modulators for producing medicaments, and to pharmaceutical compositions which comprise these compounds.

The steroid hormone progesterone controls in a decisive manner the reproductive process in the female body. Progesterone is secreted in large quantities during the cycle and pregnancy respectively by the ovary and the placenta. Progesterone in cooperation with oestrogens brings about cyclic changes in the uterine mucosa (endometriur) during the menstrual cycle. Elevated progesterone levels after ovulation influence the uterine mucosa to convert it into a state permitting nidation of an embryo (blastocyst). During pregnancy, progesterone controls the relaxation of the myometrium and maintains the function of the decidual tissue.

It is further known that progesterone inhibits endometrial proliferation by suppressing oestrogen-mediated mitosis in uterine tissue (K. Chwalisz, R. M. Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741-751).

Progesterone and progesterone receptors are also known to play a significant part in pathophysiological processes. Progesterone receptors have been detected in the foci of endometriosis, but also in tumours of the uterus, of the breast and of the CNS. It is further known that uterine leiomyomas grow progesterone-dependently.

The effects of progesterone in the tissues of the genital organs and in other tissues occur through interactions with progesterone receptors which are responsible for the cellular effects.

Progesterone receptor modulators are either pure agonists or inhibit the effect of progesterone partly or completely. Accordingly, substances are defined as pure agonists, partial agonists (SPRMs) and pure antagonists.

In accordance with ability of progesterone receptor modulators to influence the effect of the progesterone receptor, these compounds have a considerable potential as therapeutic agents for gynaecological and oncological indications and for obstetrics and fertility control.

Pure progesterone receptor antagonists completely inhibit the effect of progesterone on the progesterone receptor. They have anti-ovulatory properties and the ability to inhibit oestrogen effects in the endometrium, as far as complete atrophy. They are therefore particularly suitable for intervening in the female reproductive process, e.g. post-ovulation, in order to prevent nidation, during pregnancy in order to increase the reactivity of the uterus to prostaglandins or oxytocin, or in order to achieve opening and softening (“ripening”) of the cervix, and to induce a great, readiness of myometrium to contract.

A beneficial effect on the pathological event is expected in foci of endometriosis and in tumour tissues which are equipped with progesterone receptors after administration of pure progesterone receptor antagonists. There might be particular advantages for influencing pathological states such as endometriosis or uterine leiomyomas if ovulation inhibition can additionally be achieved by the progesterone receptor antagonists. Ovulation inhibition also dispenses with some of the ovarian hormone production and thus the stimulating effect, deriving from this proportion, on the pathologically altered tissue.

The first progesterone receptor antagonist described, RU 486 (also mifepristone), was followed by a large number of analogues with progesterone receptor-antagonistic activity of varying strength. Whereas RU 486 shows an antiglucocorticoid effect in addition to the progesterone receptor-antagonistic effect, compounds synthesized later are notable in particular for a more selective effect as progesterone receptor antagonists.

Besides steroidal compounds such as onapristone or lilopristone, which are notable by comparison with RU 486 for a better dissociation of the progesterone receptor-antagonistic effect and the antiglucocorticoid effect, also known from the literature are various non-steroidal structures whose antagonistic effect on the progesterone receptor is being investigated [see, for example, S. A. Leonhardt and D. P. Edwards, Exp. Biol. Med. 227: 969-980 (2002) and R. Winneker, A. Fensome, J. E. Wrobel, Z. Zhang, P. Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)]. However, compounds disclosed to date have only moderate antagonistic activity compared with the known steroidal structures. The most effective non-steroidal compounds are reported to have in vitro activities which are 10% of the activity of RU 486.

The antiglucocorticoid activity is disadvantageous for therapeutic use, where the inhibition of progesterone receptors is at the forefront of the therapy. An antiglucocorticoid activity causes unwanted side effects at the dosages necessary for therapy. This may prevent administration of a therapeutically worthwhile dose or lead to discontinuation of the treatment.

Partial or complete reduction of the antiglucocorticoid properties is therefore an important precondition for therapy with progesterone receptor antagonists, especially for those indications requiring treatment lasting weeks or months.

In contrast to the pure antagonists, partial progesterone receptor agonists (SPRMs) show a residual agonistic property which may vary in strength. This leads to these substances showing potentially agonistic effects on the progesterone receptor in certain organ systems (D. DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess-Stumpp, G. Schuber, K. Chwalisz, Steroids 68, 2003, 1019-1032). Such an organ-specific and dissociated effect may be of therapeutic benefit for the described indications.

It is therefore an object of the present invention to provide further non-steroidal progesterone receptor modulators. These compounds are intended to have a reduced antiglucocorticoid effect and therefore be suitable for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. The compounds according to the invention are additionally intended to be suitable for the therapy and prophylaxis of hormone-dependent tumours, for example of breast, endometrial, ovarian and prostate carcinomas. The compounds are intended furthermore to be suitable for use in female fertility control and for female hormone replacement therapy.

The object is achieved according to the present invention by the provision of non-steroidal compounds of the general formula I

in which

-   R¹ and R² are independently of one another a hydrogen atom, a linear     or nonlinear, branched or unbranched C₁-C₅-alkyl group, further     forming together with the C atom of the chain a ring having a total     of 3-7 members, -   R³ is a radical C≡C—R^(a), where     -   R^(a) is a hydrogen or a C₁-C₈-alkyl, C₂-C₈-alkenyl,         C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl, heterocycloalkyl optionally         substituted one or more times, identically or differently, by K,         or an aryl or heteroaryl optionally substituted one or more         times, identically or differently by L,         -   K is a cyano, halogen, hydroxy, nitro, —C(O)R^(b), CO₂R^(b),             —O—R^(b), —S—R^(b), SO₂NR^(c)R^(d), —C(O)—NR^(c)R^(d),             —OC(O)—NR^(c)R^(d), —C═NOR^(b)—NR^(c)R^(d) or             C₃-C₁₀-cycloalkyl, heterocycloalkyl optionally substituted             one or more times, identically or differently, by M, or aryl             or heteroaryl optionally substituted one or more times by L,         -   L is C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,             C₁-C₆-perfluoroalkyl, C₁-C₆-perfluoroalkoxy,             C₁-C₆-alkoxy-C₁-C₆-alkoxy, (CH₂)_(p)—C₃-C₁₀-cycloalkyl,             (CH₂)_(p)-heterocycloalkyl, (CH₂)_(p)CN, (CH₂)_(p)Hal,             (CH₂)_(p)NO₂, (CH₂)_(p)—C₆-C₁₂-aryl, (CH₂)_(p)-heteroaryl,             —(CH₂)_(p)PO₃(R^(b))₂,             -   —(CH₂)_(p)NR^(c)R^(d), (CH₂)NR^(e)COR^(b),                 —(CH₂)_(p)NR^(e)CSR^(b), (CH₂)_(p)NR^(e)S(O)R^(b),                 —(CH₂)_(p)NR^(e)S(O)₂R^(b);                 —(CH₂)_(p)NR^(e)CONR^(c)R^(d), —(CH₂)_(p)NR^(e)COOR^(b),                 —(CH₂)_(p)NR^(e)C(NH)NR^(c)R^(d),                 —(CH₂)_(p)NR^(e)CSNR^(c)R^(d),                 —(CH₂)_(p)NR^(e)S(O)NR^(c)R^(d),                 —(CH₂)_(p)NR^(e)S(O)₂NR^(c)R^(d), —(CH₂)_(p)COR^(b),                 —(CH₂)_(p)SR^(b), —(CH₂)PS(O)R^(b),                 —(CH₂)PS(O)(NH)R^(b), —(CH₂)_(p)S(O)₂R^(b),                 —(CH₂)_(p)S(O)₂NR^(c)R^(d), —(CH₂)_(p)SO₂OR^(b),                 —(CH₂)_(p)CO₂R^(b), —(CH₂)_(p)CONR^(c)R^(d),                 —(CH₂)_(p)CSNR^(c)R^(d), —(CH₂)_(p)OR^(b),                 —(CH₂)_(p)SR^(b), —(CH₂)_(p)CR^(b)(OH)—Re,                 —(CH₂)_(p)—C═NOR^(b), —O—(CH₂), —O—, —O—(CH₂), —CH₂—,                 —O—CH═CH— or —(CH₂)_(n+2)—, where n is 1 or 2, and the                 terminal oxygen atoms and/or carbon atoms are linked to                 directly adjacent ring carbon atoms,         -   M is C₁-C₆-alkyl or a group —COR^(b), CO₂R^(b), —O—R^(b), or             —NR^(c)R^(d), where             -   R^(b) is a hydrogen or a C₁-C₆-alkyl, C₂-C₈-alkenyl,                 C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl, C₆-C₁₂-aryl or                 C₁-C₃-perfluoroalkyl and             -   R^(c) and R^(d) are independently of one another a                 hydrogen, C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,                 C₃-C₁₀-cycloalkyl, C₆-C₁₂-aryl, C(O)R^(b) or a hydroxy                 group, where if             -   R^(c) is a hydroxy group, then R^(d) can only be a                 hydrogen, a C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,                 C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl and vice versa, and             -   R^(e) is a hydrogen, C₁-C₆-alkyl, C₂-C₈-alkenyl,                 C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl, and             -   p can be a number from 0-6, -   or -   R³ is a radical C═C—R^(g)R^(h), where     -   R⁹ and R^(h) are independently of one another a hydrogen or a         C₁-C₈-alkyl, C₂-C₈-alkenyl or C₂-C₈-alkynyl optionally         substituted one or more times, identically or differently, by X,         in which         -   X is a cyano, halogen, hydroxy, nitro, —C(O)R^(b), CO₂R^(b),             —O—R^(b), —C(O)—NR^(c)R^(d), —NR^(c)R^(d) with the meanings             already mentioned-before for R^(b), R^(c) and R^(d), and -   R⁴ is a hydrogen atom, a methyl or an ethyl group or a partly or     completely fluorinated C₁-C₃-alkyl group, -   A is a mono- or bicyclic carbocyclic or heterocyclic aromatic ring     which may optionally be substituted one or more times by     C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₁-C₆-perfluoroalkyl,     C₁-C₆-perfluoroalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,     C₁-C₆-alkoxy-C₁-C₆-alkoxy, (CH₂)_(p)—C₃-C₁₀-cycloalkyl,     (CH₂)_(p)-heterocycloalkyl, (CH₂)_(p)CN, (CH₂)_(p)Hal, (CH₂)_(p)NO₂,     (CH₂)_(p)—C₆-C₁₂-aryl, (CH₂)_(p)-heteroaryl,     -   —(CH₂)_(p)PO₃(R^(b))₂, —(CH₂)_(p)NR^(c)R^(d),         —(CH₂)_(p)NR^(e)COR^(b), (CH₂)_(p)NR^(e)CSR^(b);         (CH₂)_(p)NR^(e)S(O)R^(b), —(CH₂)_(p)NR^(e)S(O)₂R^(b),         —(CH₂)_(p)NR^(e)CONR^(c)R^(d), —(CH₂)_(p)NR^(e)COOR^(b),         —(CH₂)_(p)NR^(e)C(NH)NR^(c)R^(d), —(CH₂)_(p)NR^(e)CSNR^(c)R^(d),         —(CH₂)_(p)NR^(e)S(O)NR^(c)R^(d),         —(CH₂)_(p)NR^(e)S(O)₂NR^(c)R^(d), —(CH₂)_(p)COR^(b),         —(CH₂)_(p)CSR^(b), —(CH₂)_(p) S(O)R^(b),         —(CH₂)_(p)S(O)(NH)R^(b), —(CH₂)_(p)S(O)₂R^(b),         —(CH₂)_(p)S(O)₂NR^(c)R^(d), —(CH₂)_(p)SO₂OR^(b),         —(CH₂)_(p)CO₂R^(b), —(CH₂)_(p)CONR^(c)R^(d),         —(CH₂)_(p)CSNR^(c)R^(d), —(CH₂)_(p)OR^(b), —(CH₂)_(p)SR^(b),         —(CH₂)_(p)CR^(b)(OH)—R^(d), —(CH₂)_(p)—C═NOR^(b),         —O—(CH₂)_(n)—O—, —O—(CH₂), —CH₂—, —O—CH═CH— or —(CH₂)_(n+2)—,         where n is 1 or 2, and the terminal oxygen atoms and/or carbon         atoms are linked to directly adjacent ring carbon atoms, or -   A is a radical —CO₂R^(b), C(O)NR^(c)R^(d), COR^(b), -   or -   A is an alkenyl group —CR⁵═CR⁶R⁷, where     -   R⁵, R⁶ and R⁷ are identical or different and are independently         of one another hydrogen atoms, halogen atoms, aryl radicals or         an unsubstituted or partly or completely fluorinated C₁-C₅-alkyl         group, or -   A is an alkynyl group —C≡CR⁵, with the meaning stated above for R⁵,     and -   B is a carbonyl or a CH₂ group,     and their pharmaceutically acceptable salts.

The compounds according to the invention of the general formula I may, owing to the presence of centres of asymmetry, exist as different stereoisomers. Both the racemates and the separate stereoisomers belong to the subject matter of the present invention.

The present invention further includes the novel compounds as active pharmaceutical ingredients, the preparation thereof, their therapeutic use and pharmaceutical dosage forms which comprise the novel substances.

The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts can be used to produce a medicament, in particular for the treatment and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. The compounds according to the invention may further be used for the treatment and prophylaxis of hormone-dependent tumours such as, for example, for breast, prostate and endometrial carcinoma.

The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts are suitable for use for female fertility control or for female hormone replacement therapy.

The present invention additionally relates to a process for preparing the compounds of the general formula (I). The substituent R³ is introduced by selective addition reaction of organometallic compounds such as lithium alkynyls or magnesium haloalkynyls onto a keto group. This leads either directly or after carrying out further modificiations to the compounds according to the invention of the general formula (I).

The compounds according to the invention are prepared by selective addition of organometallic compounds onto keto amides which have been described for example in the published specifications US 2002/0077356, U.S. Pat. No. 6,323,199B1, WO 200375915 and WO 9854159. The organometallic compounds may be for example lithium alkynyl or magnesium haloalkynyl compounds. These are generated for example by reacting the appropriate alkynes with butyllithium or Grignard compounds. The corresponding organometallic alkenyl compounds can also be prepared in analogy thereto. The reactivity of the keto groups is in this case distinctly higher by comparison with the amide carbonyl and with the benzoxazinone, so that a selective addition is achieved on suitable choice of the reaction conditions. Alternatively, the alkynyl or alkenyl radicals introduced as R³ can also be further modified later. Reactions suitable for these modifications are those known to the skilled person, such as oxidation, reduction, substitution, alkylation, palladium-catalysed reaction. Any protective groups present are eliminated at a suitable time.

The non-steroidal compounds according to the invention of the general formula I have strong antagonistic or strong partial agonistic effects on the progesterone receptor: They show a strong dissociation of effects in relation to their strength of binding to the progesterone receptor and to the glucocorticoid receptor. Whereas known progesterone receptor antagonists such as mifepristone (RU 486) show, besides the desired high binding affinity for the progesterone receptor, likewise a high affinity for the glucocorticoid receptor, the compounds according to the invention are notable for a very low glucocorticoid receptor binding with simultaneously a high progesterone receptor affinity.

The substituents, defined as groups, of the compounds according to the invention of the general formula I may in each case have the following meanings:

C₁-C₅-, C₁-C₆- and C₁-C₈-alkyl group means linear or nonlinear, branched or unbranched alkyl radicals. Examples thereof are a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, an n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl group.

Preferred in the meaning of R^(a) in this connection are the methyl, ethyl, n-propyl or n-butyl group and an n-pentyl group.

Preferred in the meaning of R¹ and R² are methyl or ethyl.

Alkenyl means linear or nonlinear, branched or unbranched alkenyl radicals. Examples of the meaning of a C₂-C₈-alkenyl group in the context of the invention are the following: vinyl, allyl, 3-buten-1-yl or 2,3-dimethyl-2-propenyl. If the aromatic system A is substituted by a C₂-C₈-alkenyl radical, it is preferably a vinyl group.

Alkynyl means linear or nonlinear, branched or unbranched alkynyl radicals. A C₂-C₈-alkynyl radical is intended to be for example an ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl group, preferably an ethynyl or propynyl group.

Examples which may be mentioned of C₃-C₁₀-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

Heterocycloalkyl in the meaning of R^(a), K and L means 3-8-membered heterocycloalkyl radicals. Examples of heterocycloalkyl are morpholinyl, tetrahydrofuranyl, pyranyl, piperazinyl, piperidinyl, pyrrolidinyl, oxiranyl, oxetanyl, aziridinyl, dioxolanyl and dioxanyl. In this connection, the position of the heteroatom in relation to the point of linkage can be any chemically possible position.

Possible examples of C₁-C₆-alkoxyl-C₁-C₆-alkoxy group are methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy.

A radical OR^(b) in the context of the invention is a hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-, iso-, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy or 3-methylbutoxy group. Hydroxy, methoxy and ethoxy are preferred.

Suitable for a partly or completely fluorinated C₁-C₅-alkyl group are the perfluorinated alkyl groups above. Of these, preference is given in particular to the trifluoromethyl or pentafluoroethyl group and, partly fluorinated alkyl groups, for example the 5,5,5,4,4-pentafluoropentyl or 5,5,5,4,4,3,3-heptafluoropentyl group.

A halogen atom may be a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine or bromine is preferred here.

If R¹ and R² form together with the C atom of the chain a 3-7 membered ring, this is for example a cyclopropyl, -butyl, -pentyl or -hexyl ring. The cyclopropyl and the cyclopentyl ring are preferred.

The mono- or bicyclic carbocyclic aromatic ring A, which may be substituted more than once, is a carbocyclic or heterocyclic aryl radical.

In the former case it is for example a phenyl or naphthyl radical, preferably a phenyl radical.

It is possible to use as heterocyclic radical for example a monocyclic heterocyclic radical, for example the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radical, in particular all the possible isomers in relation to the positions of the heteroatoms.

R³ means in the case of an aryl radical an optionally substituted phenyl, 1- or 2-naphthyl radical, with preference for the phenyl radical. Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.

The number p for a (CH₂)_(p) radical may be a number from 0 to 6, preferably 0 to 2. “Radical” means according to the invention all functional groups stated in connection with (CH₂)_(p).

In the case where the compounds of the general formula I (B=—CH₂—) are in the form of salts, this is possible for example in the form of the hydrochloride, sulphate, nitrate, tartrate, citrate, fumarate, succinate or benzoate.

If the compounds according to the invention are in the form of racemic mixtures, they can be fractionated by methods of racemate resolution familiar to the skilled person into the pure optically active forms. For example, the racemic mixtures can be separated into the pure isomers by chromatography on a support material which is itself optically active (CHIRALPAK AD®). It is also possible to esterify the free hydroxy group in a racemic compound of the general formula I with an optically active acid, and to separate the resulting diastereoisomeric esters by fractional crystallization or chromatography and to hydrolyse the separated esters in each case to the optically pure isomers. It is possible to use as optically active acid for example mandelic acid, camphorsulphonic acid or tartaric acid.

The compounds specified below, and the use thereof, are preferred according to the invention: Racemic or No. enantiomer R3

1 2 3 rac −+

4 5 6 rac −+

7 8 9 rac −+

10 11 12 rac −+

13 14 15 rac −+

16 17 18 rac −+

19 20 21 rac −+

22 23 24 rac −+

25 26 27 rac −+

28 29 30 rac −+

31 32 33 rac −+

34 35 36 rac −+

37 38 39 rac −+

40 41 42 rac −+

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49 50 51 rac −+

52 53 54 rac −+

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541 542 543 rac −+

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547 548 549 rac −+

550 551 552 rac −+

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568 569 570 rac −+

571 572 573 rac −+

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577 578 579 rac −+

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583 584 585 rac −+

586 587 588 rac −+

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628 629 630 rac −+

631 632 633 rac −+

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Biological Characterization of the Compounds According to the Invention

Progesterone receptor modulators can be identified with the aid of simple methods, test programmes known to the skilled person. It is possible for this purpose for example to incubate a compound to be tested together with a progestogen in a test system for progesterone receptors and to check whether the effect mediated by progesterone is altered in the presence of the modulator in this test system.

The substances according to the invention of the general formula I were tested in the following models:

Progesterone Receptor-Binding Assay

Measurement of the Receptor Binding Affinity:

The receptor binding affinity was determined by competitive binding of a specifically binding ³H-labelled hormone (tracer) and of the compound to be tested on receptors in the cytosol from animal target organs. The aim in this case was receptor saturation and reaction equilibrium.

The tracer and increasing concentrations of the compound to be tested (competitor) were coincubated at 0-4° C. for 18 h with the receptor-containing cytosol fraction. After removal of unbound tracer with carbon-dextran suspension, the receptor-bound tracer content was measured for each concentration, and the IC₅₀ was determined from the concentration series. The relative molar binding affinity (RBA) was calculated as ratio of the IC₅₀ values for reference substance and compound to be tested (×100%) (RBA of the reference substance=100%).

The following incubation conditions were chosen for the receptor types:

Progesterone Receptor:

Uterus cytosol of the estradiol-primed rabbit, homogenized in TED buffer (20 mMTris/HCl, pH 7.4; 1 mM ethylenediaminetetraacetate, 2 mM dithiothreitol) with 250 mM sucrose; stored at −30° C. Tracer: ³H-ORG 2058, 5 nM; reference substance: progesterone.

Glucocorticoid Receptor:

Thymus cytosol from the adrenalectomized rat, thymi stored at −30° C.; buffer: TED. Tracer: ³H-dexamethasone, 20 nM; reference substance: dexamethasone.

The relative receptor binding affinities (RBA values) for the compounds according to the invention of the general formula (I) on the progesterone receptor are between 3 and 100% relative to progesterone. The RBA values at the glucocorticoid receptor are in the range from 3 to 30% relative to dexamethasone.

The compounds according to the invention accordingly have a high affinity for the progesterone receptor, but only a low affinity for the glucocorticoid receptor.

Antagonism at the PR-B Progesterone Receptor

The transactivation assay is carried out as described in WO 02/054064.

Agonism on the PR-B Progesterone Receptor

The transactivation assay is carried out as described in Fuhrmann et al. (Fuhrmann U., Hess-Stump H., Cleve A., Neef G., Schwede W., Hoffmann J., Fritzemeier K.-H., Chwalisz K., Journal of Medicinal Chem, 43, 26, 2000, 5010-5016). Antagonistic Activity Agonistic Acticity No. IC₅₀ [nM] Efficacy [%] EC₅₀ [nM] Efficacy [%]  5 0.2 86 0.2 10 14 6 53 7 35 16 0.7 82 0.5 13 17b 0.03 88 n.b. 7 18 0.2 89 n.b. 8 24 2 100 0 35 2 100 0 Dosage

The progesterone receptor modulators can be administered orally, enterally, parenterally or transdermally for the use according to the invention.

Satisfactory results are generally to be expected in the treatment of the indications mentioned hereinbefore when the daily doses cover a range from 1 μg to 500 mg of the compound according to the invention.

Suitable dosages of the compounds according to the invention in humans for the treatment of endometriosis, of leiomyomas of the uterus and dysfunctional bleeding and for use in fertility control and for hormone replacement therapy are from 50 μg to 500 mg per day, depending on the age and constitution of the patient, it being possible to administer the necessary daily dose by single or multiple administration.

The dosage range for the compounds according to the invention for the treatment of breast carcinomas is 10 mg to 1000 mg per day.

The pharmaceutical products based on the novel compounds are formulated in a manner known per se by processing the active ingredient with the carrier substances, fillers, substances influencing disintegration, binders, humectants, lubricants, absorbents, diluents, masking flavours, colorants, etc. which are used in pharmaceutical technology, and converting into the desired administration form. Reference should be made in this connection to Remington's Pharmaceutical Sciences, 15^(th) ed. Mack Publishing Company, Easton, Pa. (1980).

Suitable for oral administration are in particular tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions.

Preparations for injection and infusion are possible for parenteral administration.

Appropriately prepared crystal suspensions can be used for intraarticular injection.

Aqueous and oily solutions for injection or suspensions and corresponding depot preparations can be used for intramuscular injection.

For rectal administration, the novel compounds can be used in the form of suppositories, capsules, solutions (e.g. in the form of enemas) and ointments, both for systemic and for local therapy.

Furthermore, compositions for vaginal use may also be mentioned as preparation.

For pulmonary administration of the novel compounds, they can be used in the form of aerosols and inhalants.

Patches are possible for transdermal administration, and formulations in gels, ointments, fatty ointments, creams, pastes, dusting powders, milk and tinctures are possible for topical application. The dosage of the compounds of the general formula I in these preparations should be 0.01%-20% in order to achieve an adequate pharmacological effect.

Corresponding tablets can be obtained for example by mixing active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as maize starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or means to achieve a depot effect such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of a plurality of layers.

Correspondingly, coated tablets can be produced by coating cores produced in analogy to the tablets with compositions normally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. The tablet covering may in this case also consist of a plurality of layers, it being possible to use the excipients mentioned above for tablets.

Solutions or suspensions of the compounds according to the invention of the general formula I may additionally comprise taste-improving agents such as saccharin, cyclamate or sugar, and, for example, flavourings such as vanillin or orange extract. They may additionally comprise suspending excipients such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.

Capsules comprising the compounds of the general formula I can be produced for example by mixing the compound(s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it in gelatin capsules.

Suitable suppositories can, be produced for example by mixing with carriers intended for this purpose, such as neutral fats or polyethylene glycol or derivatives.

The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts can be used, because of their antagonistic or partial agonistic activity, for producing a medicament, in particular for the treatment and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. They can furthermore be employed to counteract hormonal irregularities, for inducing menstruation and alone or in combination with prostaglandins and/or oxytocin to induce labour.

The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts are furthermore suitable for producing products for female contraception (see also WO 93/23020, WO 93/21927).

The compounds according to the invention or their pharmaceutically acceptable salts can additionally be employed alone or in combination with a selective estrogen receptor modulator (SERM) for female hormone replacement therapy.

In addition, the said compounds have an antiproliferative effect in hormone-dependent tumours. They are therefore suitable for the therapy of hormone-dependent carcinomas such as, for example, for breast, prostate and endometrial carcinomas.

The compounds according to the invention or their pharmaceutically acceptable salts can be employed for the treatment of hormone-dependent carcinomas both in first-line therapy and in second-line therapy, especially after tamoxifen failure.

The compounds according to the invention, having antagonistic or partially agonistic activity, of the general formula (I) or their pharmaceutically acceptable salts can also be used in combination with compounds having antiestrogenic activity (estrogen receptor antagonists or aromatase inhibitors) or selective estrogen receptor modulators (SERM) for producing pharmaceutical products for the treatment of hormone-dependent tumours. The compounds according to the invention can likewise be used in combination with SERMs or an antiestrogen (estrogen receptor antagonist or aromatase inhibitor) for the treatment of endometriosis or of leiomyomas of the uterus. In the treatment of hormone-dependent tumours the progesterone receptor modulator and the antiestrogen (estrogen receptor antagonists or aromatase inhibitors) or the SERM can be provided for simultaneous or else for sequential administration. In the sequential administration, preferably the antiestrogen (estrogen receptor antagonists or aromatase inhibitors) or SERM is administered first and subsequently the progesterone receptor modulator is administered.

Suitable for combination with the non-steroidal progesterone receptor modulators according to the invention in this connection are for example the following antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs: tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulphinyl]pentyloxy}phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha-[9-(4,4,5,5-pentafluoropentylsulphinyl)nonyl]estra-1,3,5(10)-triene-3,17beta-diol), 11beta-fluoro -7alpha-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulphanyl]propyl}amino)pentyl]-estra-1,3,5(10)-triene-3,17beta-diol (WO98/07740), 11beta-fluoro-7alpha-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17-beta-diol (WO 99/33855), 11beta-fluoro-17alpha-methyl-7alpha-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol (WO 03/045972), clomifen, raloxifen, and further compounds having antiestrogenic activity, and aromatase inhibitors such as, for example, fadrozole, formestane, letrozole, anastrozole or atamestane.

Finally, the present invention also relates to the use of the compounds of the general formula I, where appropriate together with an antiestrogen or SERM, for producing a medicament.

The present invention further relates to pharmaceutical compositions which comprise at least one compound according to the invention, where appropriate in the form of a pharmaceutically/pharmacologically acceptable salt, without or together with pharmaceutically acceptable excipients and/or carriers.

These pharmaceutical compositions and medicaments may be intended for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration. Besides conventional carriers and/or diluents, they comprise at least one compound according to the invention.

The medicaments of the invention are produced with the conventional solid or liquid carriers or diluents and the excipients normally used in pharmaceutical technology appropriate for the desired mode of administration with a suitable dosage in a known manner. The preferred preparations consist of a dosage suitable for oral administration. Examples of such dosage forms are tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, solutions or suspensions or else depot forms.

The pharmaceutical compositions comprising at least one of the compounds according to the invention are preferably administered orally.

Also suitable are parenteral preparations such as solutions for injection. Further preparations which may also be mentioned are for example suppositories and compositions for vaginal use.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.

The following examples serve to illustrate the subject-matter of the invention in more detail without wishing to restrict it thereto.

Preparation of the starting compounds 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one, 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one and 6-{3-[1-(2-chlorophenyl)cyclopentyl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-one has been described in the patent US 2002/0077356, the compound 6-[4-(2,3-dihydro-7-benzofuranyl)-4-methyl-2-oxopentanoylamino]-4-methyl-2,3-benzoxazinone in U.S. Pat. No. 6,323,199B1 (example 87 therein), the compound 6-(4-methyl-4-phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one in the patent WO 199854159 and the compound 6-[3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionylamino]-4-methyl-2,3-benzoxazin-1-one in the patent WO 200375915.

General Methods

1-(Benzo[1,3]dioxol-4-yl)-1-methylethanol

57.2 ml of methyl magnesium chloride solution (3M in THF) were added to 25.5 g of 4-acetylbenzo[1,3]dioxole in 375 ml of THF at RT under argon. The mixture was stirred at RT for 16 h and added to ice/2N hydrochloric acid. It was then extracted with ethyl acetate, and the organic phase was washed with water and brine and dried (Na₂SO₄). 27.89 g of 1-[benzo(1,3)dioxol-4-yl]-1-methylethanol were obtained as a brown oil.

¹H-NMR (CDCl₃, ppm)=1.6 (s, 6H), 5.95 (s, 2H), 6.76 (dd, 1H), 6.82 (t, 1H), 6.91 (dd, 1H)

4-(Benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid

47 ml of tin(IV) chloride were added to 9.5 g of 1-(benzo[1,3]dioxol-4-yl)-1-methylethanol and 14.2 g of ethyl 2-trimethylsilyloxyacrylate in 200 ml of dichloromethane at −70° C. After 15 minutes, the solution was added to potassium carbonate solution. After extraction with diethyl ether, the organic phase was washed with water, dried and evaporated.

14.4 g of the ethyl 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoate obtained in this way were stirred with 150 ml of 1 M sodium hydroxide and 300 ml of methanol at RT for 10 hours. The methanol was then removed in vacuo, and the remaining solution was extracted with diethyl ether. The aqueous phase was acidified with 1 M hydrochloric acid and extracted with diethyl ether. Drying and evaporation resulted in 11.1 g of 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid as yellowish oil.

MS (ei) m/e: M⁺=251

6-[4-(Benzo[1, 3]dioxol-4-yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

10 g of 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid were dissolved in 125 ml of dimethylacetamide and, at −0° C. under argon, 3.5 ml of thionyl chloride were added. After stirring at −3 to +3° C. for 20 minutes, 7.6 g of 6-amino-4-methyl-2,3-benzoxazin-1-one (WO 00/32584) were added. The mixture was stirred at room temperature for 96 hours and, after addition of water, extracted with ethyl acetate, the organic phase was washed with water and dried (Na₂SO₄), and evaporation of the solvent and chromatography of the crude product on silica gel with hexane/ethyl acetate (100:0->60:40) resulted in 6.56 g of 6-[4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-11-one as a beige solid.

m.p.=165-166° C., MS (ei) m/e: M⁺=409

SYNTHESIS EXAMPLES (−)-6-{2-[2-(2,3-(Methylenedioxy)phenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3-benzoxazin-1-one 1 and (+)-6-{2-[2-(2,3-(methylenedioxy)phenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3-benzoxazin-1-one 2

nBuLi (0.7 ml, 1.6M in hexane) was added to a solution of 1-hexyne (0.5 ml) in THF (4 ml) at −78° C. The mixture was stirred at −78° C. for 20 min, 6-[4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (192 mg) was added, and the mixture was stirred at −78° C. for 4 h. Water was then added and the mixture was allowed to reach room temp. Extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over sodium sulphate and purification by column chromatography on silica gel resulted in 82 mg of a white foam which was then converted by preparative chiral HPLC (Chiralpak AD 250×10 mm, eluent: acetonitrile/water 55/45 v/v, flow rate 4.7 ml/min, temperature 40° C., retention times: 12.2 min (+)-enantiomer, 15.7 min (−)-enantiomer) into the compounds (−)-6-{2-[2-(2,3-(methylenedioxy)phenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3-benzoxazin-1-one (Example 1) and (+)-6-{2-[2-(2,3-(methylenedioxy)phenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3-benzoxazin-1-one (Example 2).

1H-NMR (ppm, CDCl₃, 400 MHz): 0.91 (t, J=7.2 Hz, 3H, CH₃), 1.32-1.49 (m, 4H), 1.55 (s, 3H), 1.58 (s, 3H), 2.17 (t, J=7.2 Hz, 2H), 2.56 (s, 3H, CH₃), 2.59 (d, J=14.4 Hz, 1H), 2.74 (d, J=14.8 Hz, 1H), 2.80 (s, 1H, OH), 5.94-5.96 (m, 2H), 6.46-6.49 (m, 1H), 6.64 (t, J=7.8 Hz, 1H), 7.47-7.49 (m, 1H), 8.25-8.28 (m, 1H), 8.76 (s, 1H, NH). C₂₈H₃₀N₂O₆ (490.6):

rac-6-{2-[2-(2-Chloro-5-fluorophenyl)-2-methylpropyl]-2,7-dihydroxyhept-3-ynoyl}-4-methyl-2,3-benzoxazin-1-one 3

Stage A: Reaction of 5-(tert-butyldimethylsilyloxy)pent-1-yne (531 mg), nBuLi (0.7 ml, 1.6 M in hexane) and 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (207 mg) at −78° C. as described for Example 1 gave, after column chromatography on silica gel, a colourless oil (86 mg).

Stage B: The resulting oil was stirred in THF (3 ml) at room temp. under argon (3 h). Addition of water, extraction with ethyl acetate and washing with saturated brine were followed by drying with sodium sulphate. Purification by column chromatography on silica gel led to the title compound as a white foam (43 mg).

1H-NMR (ppm, CDCl₃, 400 MHz): 1.58 (s, 3H, Me), 1.59 (s, 3H, Me), 1.71-1.74 (m, 2H, CH₂), 2.2-2.3 (m, 2H), 2.56 (s, 3H, CH₃), 2.75 (d, J=15.2 Hz, 1H, CH), 2.92 (d, J=14.8 Hz, 1H, CH), 3.26 (s, 1H, OH), 3.74-3.78 (m, 2H), 6.67-6.78 (m, 1H), 7.09-7.19 (m, 2H), 7.66-7.69 (m, 2H), 8.20-8.21 (m, 1H), 8.27-8.29 (m, 1H), 8.99 (s, 1H, NH). C₂₆H₂₆ClFN₂O₅ (501.0): LC-MS: m/z=501 [M+H⁺].

rac-6-{2-[2-(2-Chloro-5-fluorophenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3-benzoxazin-1-one 4

Reaction of 1-hexyne (0.6 ml), nBuLi (0.7 ml, 1.6 M in hexane) and 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (207 mg) at −78° C. as described for Example 1 gave, after column chromatography on silica gel and preparative thin-layer chromatography a viscous oil (12 mg).

1H-NMR (ppm, CDCl₃, 400 MHz): 0.90 (t, J=7.2 Hz, 3H, Me), 1.32-1.47 (m, 4H), 1.57 (s, 3H, Me), 1.62 (s, 3H, Me), 2.13 (t, J=7.2 Hz, CH₂C≡C), 2.56 (s, 3H, Me), 2.81-2.95 (m, 3H), 6.68-6.71 (m, 1H), 7.11-7.17 (m, 2H), 7.56-7.58 (m, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.29 (d, J=12.6 Hz, 1H), 8.73 (br. s., 1H, NH). C₂₇H₂₈ClFN₂O₄ (499.0): LC-MS: m/z=499 [M+H⁺].

rac-6-{2-[(2-Chlorophenyl)cyclopentyl]methyl-2-hydroxy-4-phenylbut-3-ynoylamino}-4-methyl-2,3-benzoxazin-1-one 5

Lithiumphenylacetylide (0.65 ml, 1M in THF) was added to 6-{3-[1-(2-chlorophenyl)cyclopentyl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-one (110 mg) at −78° C. and allowed to reach room temperature under argon during the night. Working up as described for Example 1 and column chromatography on silica gel resulted in the title compound as a foam (54 mg) after oil-pump drying. ¹H-NMR (ppm, CDCl₃, 400 MHz): 1.59-1.85 (m, 5H), 2.18-2.35 (m, 3H), 2.54 (s, 3H, Me), 2.7-3.09 (3H), 6.94-7.58 (m, 10H), 8.18 (d, J=1.1 Hz), 8.25 (d, J=8.6 Hz, 1H), 8.81 (br. s., 1H, NH). C₃₁H₂₇ClN₂O₄ (526.0): HPLCMS: m/z=526 [M], purity 97%.

6-{2-[2-(2,3-Dihydro-7-benzofuranyl)-2-methylpropyl]-2-hydroxy-3-octynoylamino}-4-methyl-2,3-benzoxazin-1-one 6

Reaction of 1-hexyne (0.4 ml), nBuLi (0.7 ml, 1.6 M in hexane) and 6-[4-(2,3-dihydro-7-benzofuranyl)-4-methyl-2-oxopentanoylamino]-4-methyl-2,3-benzoxazin-1-one (99.5 mg) at −78° C. in THF (3 ml) as described for Example 1 gave, after column chromatography on silica gel and drying in vacuo, a solidified colourless oil (42 mg). 1H NMR (ppm, CDCl₃, 400 MHz): 0.89 (t, J=7.2 Hz, 3H, Me), 1.35-1.56 (m, 10H), 2.14-2.18 (m, 2H), 2.56 (s, 3H, Me); 2.66 (d, J=14.8 Hz, 1H), 2.73 (d, J=14.8 Hz,

1H), 3.0-3.2 (m, 2H), 3.27 (s, 1H), 4.57 (t, J=9.3 Hz, 2H), 6.75 (t, J=7.5 Hz, 1H), 6.95 (d, J=6.3 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 7.50-7.52 (m, 1H), 8.23-8.29 (m, 2H), 8.78 (br. s., NH). C₂₉H₃₂ClN₂O₅ (488): LC-MS: m/z=489 [M+H⁺].

rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-2-[(4-hydroxyphenyl)ethynyl]-4-methylpentanoylamino}-4-methyl-2,3-benzoxazin-1-one 7

Stage A: a suspension of the compound of Example 10 (57.8 mg), triphenylphosphine (6.8 mg), copper iodide (5 mg), 4-iodophenyl acetate (51 mg), 5 mg of palladium acetate in THF (1 ml) and triethylamine. (3 ml) was reacted in an ultrasonic bath under argon for 1 h. Addition of saturated aqueous ammonium chloride solution was followed by extraction with ethyl acetate and washing with water and brine. Drying with sodium sulphate was followed by concentration and purification by column chromatography on silica gel. A white solid (46.7 mg) was obtained. Stage B: A suspension of the compound from stage A (46.7 mg) and sodium bicarbonate (128 mg) in methanol was stirred at room temperature under argon for 6 h. A spatula tip of sodium bicarbonate was then added, and the mixture was stirred overnight. It was diluted with ethyl acetate, water was added, and separation of the phases was followed by extraction with ethyl acetate. Washing of the combined organic phases with brine, drying over sodium sulphate, concentration and column chromatography on silica gel resulted in the title compound as a viscous oil (29 mg).

1H-NMR (ppm, CDCl₃, 400 MHz): 1.63 (s, 3H, Me), 1.69 (s, 3H, Me), 2.56 (s, 3H, Me), 2.94-3.01 (m, 3H), 5.48 (br. s, 1H, OH), 6.74-6.77 (m, 2H), 6.84-6.93 (m, 2H), 7.21-7.25 (m, 2H), 7.43 (dd, J=9.0, 6.1 Hz, 1H), 7.57-7.59 (dd, J=8.6, 2.3 Hz, 1H), 8.22 -8.23 (m, 1H), 8.31 (d, J=8.6 Hz, 1H), 8.80 (br. s, 1H, NH). C₂₉H₂₄CIFN₂O_(s) (534.98): LC-MS: m/z 535 [M+H⁺].

rac-6-{2-[2-(2-Chloro-4-fluorophenyl)-2-methylpropyl]-2-hydroxydec-3-ynoylamino}-4-methyl-2,3-benzoxazin-1-one 8

Reaction of 1-octyne (0.4 ml), nBuLi (0.6 ml, 1.6 M in hexane) and 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (110 mg) in THF (3 ml) at −78° C. as described for Example 1 gave, after column chromatography on silica gel, a white solid (25 mg).

1H-NMR (ppm, CDCl₃, 400 MHz): 0.87 (t, J=7.0 Hz, 3H), 1.26-1.46 (m, 8H), 1.58 (s, 3H, Me), 1.63 (s, 3H, Me), 2.12 (t, J=7.0 Hz, CH₂C≡C), 2.56 (s, 3H, Me) 2.79-2.91 (m, 3H), 6.92-6.95 (m, 2H), 7.40 (dd, J=8.9, 6.3 Hz, 1H), 7.53 (dd, J=8.6, 1.9 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.71 (br. s., 1H, NH); C₂₉H₃₂ClFN₂O₄ (527.0): LC-MS: m/z=527 [M+H⁺].

rac-6-{2-[2-(2-Chloro-4-fluorophenyl)-2-methyl propyl]-2-hydroxy-5-phenylpent-3-ynoylamino}-4-methyl-2,3-benzoxazin-1-one 9

Reaction of 3-phenyl-1-propyne (0.17 ml), nBuLi (0.51 ml, 1.6 M in hexane) and 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (140 mg) in THF (3 ml) at −78° C. as described for Example 1 gave, after column chromatography on silica gel and drying in vacuo, a white foam (116 mg).

1H-NMR (ppm, CDCl₃, 400 MHz): 1.59 (s, 3H, Me), 1.61 (s, 3H, Me), 2.55 (s, 3H, Me), 2.79-2.95 (m, 3H), 3.4-3.6 (m, 2H, CH₂C≡C), 6.8-6.93 (m, 2H), 7.23-7.42 (m, 7H), 8.15 (d, J=2.3 Hz, 1H), 8.27 (d, J=8.6 Hz, 1H), 8.64 (br. s., 1H, NH). C₃₀H₂₆ClFN₂O₄ (533.0): LC-MS: m/z=533 [M+H⁺].

rac-6-{4-(2-Chloro-4-fluorophenyl)-2-ethynyl-2-hydroxy-4-methylpentanoylamino}-4-methyl-2,3-benzoxazin-1-one 10

Ethynylmagnesium bromide (2.2 ml, 0.5 M in THF) was added to an ice-cold solution of 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (208 mg) in THF (4 ml). Under argon, the reaction solution was allowed to reach room temperature over the course of 3 h. Working up as described in Example 1 and column chromatography on silica gel resulted in the title compound as a foam (84 mg) after oil-pump drying. ¹H-NMR (ppm, CDCl₃, 400 MHz): 0.8-0.9 (m, 1H), 1-58 (s, 3H, Me), 1.65 (s, 3H, Me), 2.56-2.96 (6H), 6.86-6.94 (m, 2H), 7.41 (dd, J=9.0, 6.2 Hz, 1H), 7.56 (dd, J=8.6, 1.9 Hz, 1H), 8.19 (d, J=1.9 Hz, 1H), 8.31 (d, J=8.6 Hz, 1H), 8.63 (br. s., 1H, NH).

C₂₃H₂₀ClFN₂O₄ (542.9): LC-MS: m/z=543 [M+H⁺].

rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-4-methyl-2-vinyl-pentanoylamino}-4-methyl-2,3-benzoxazin-1-one 11

A vinylmagnesium bromide solution (0.5 ml, 1M in THF) was injected into 6-[4-(2-chloro -4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (103 mg) in THF (3 ml) at −78° C., and the mixture was allowed to reach room temp. under argon overnight. Addition of aqueous ammonium chloride solution was followed by extraction with ethyl acetate and washing with sat. sodium chloride solution. Drying with sodium sulphate was followed by concentration in a rotary evaporator and purification by column chromatography on silica gel to result in the title compound as solidified oil (18 mg). 1H-NMR (ppm, CDCl₃, 400 MHz, selected signals): 1.53 (s, 3H, Me), 1.57 (s, 3H, Me), 2.35 (s, 1H), 2.56 (s, 3H, Me), 2.74 (d, J=15.3 Hz, 1H), 2.89 (d, J=15.3 Hz, 1H), 5.15 (d, J=10.5 Hz, 1H), 5.27 (d, J=17.6 Hz, 1H), 6.10 (dd, J=17.2, 10.6 Hz, 1H), 6.81-6.86 (m, 1H),

rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methylpentanoylamino}-4-methyl-2,3-benzoxazin-1-one 12

Reaction of 4-methoxyphenylacetylene (0.4 ml), nBuLi (0.6 ml, 1.6 M in hexane) and 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (110 mg) at −78° C. as described for Example 1 gave, after column chromatography on silica gel, the title compound as a white solid (44 mg).

1H-NMR (ppm, CDCl₃, 400 MHz): 1.63 (s, 3H, Me), 1.69 (s, 3H, Me), 2.91-3.01. (m, 3H), 3.81 (s, 3H, Me), 6.81-6.94 (m, 3H), 7.25-7.29 (m, 3H), 7.43 (dd, J=8.4, 6.3 Hz, 1H), 7.58 (dd, J=8.6, 2.3 Hz, 1H), 8.24 (d, J=1.9 Hz, 1H), 8.31 (d, J=8.6 Hz, 1H), 8.79 (br. s., 1H, NH). C₃₀H₂₆ClFN₂O₅ (549.0): LC-MS: m/z=549 [M+H⁺].

rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-4-methyl-2-(phenylethynyl)pentanoylamino}-4-methyl-2,3-benzoxazin-1-one 13

Lithium phenylacetylide (0.65 ml, 1M in THF) was added to 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (136 mg) at. −78° C. and the mixture was stirred at −78° C. under argon for 2.5 h. Working up as described for Example 1 and column chromatography on silica gel resulted in the title compound as a white foam (102 mg) after oil-pump drying.

1H-NMR (ppm, CDCl₃, 400 MHz): 1.64 (s, 3H, Me), 1.70 (s, 3H, Me), 2.57 (s, 3H, Me), 2.92-3.03 (m, 3H), 6.82-6.86 (m, 1H), 6.91-6.93 (m, 1H), 7.30-7.36 (m, 5H), 7.44 (dd, J=9.0, 6.2 Hz, 1H), 7.59 (dd, J=8.6, 2.0 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.79 (br. s., NH); C₂₉H₂₄ClFN₂O₄ (519.0): HPLC-MS: m/z=518 [M].

The compounds 14 and 15 were prepared in analogy to Example 10 from 6-(4-methyl -4-phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the alkynyl-magnesium halide:

rac-6-[2-Ethynyl-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 14

1H-NMR (ppm, CDCl₃, 400 MHz): 1.42 (3H), 1.59 (3H), 2.57 (3H), 2.64 (4H), 7.15 (1H), 7.31 (2H), 7.46 (2H), 7.58 (1H), 8.25 (1H), 8.30 (1H), 8.81 (1H).

rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-propynylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 15

1H-NMR (ppm, CDCl₃, 400 MHz): 1.42 (3H), 1.59 (3H), 2.50-2.65 (6H), 7.11 (1H), 7.30 (2H), 7.43 (2H), 7.58 (1H), 8.29 (2H), 8.85 (1H).

The compounds 15-28 were prepared in analogy to Example 1 from 6-(4-methyl-4-phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the respective lithium arylacetylide:

rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-(phenylethynyl)pentanoylamino]-4-methyl -2,3-benzoxazin-1-one 16

1H-NMR (ppm, CDCl₃, 300 MHz): 1.47 (3H), 1.65 (3H), 2.57 (3H), 2.62-2.78 (3H), 7.15 (1H), 7.27-7.37 (5H), 7.40 (2H), 7.50 (2H), 7.59 (1H), 8.29 (2H), 8.90 (1H).

(+)-6-[2-Hydroxy-4-methyl-2-[(4-methyl phenyl)ethynyl]-4-phenyl pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 17a and (−)-6-[2-Hydroxy-4-methyl-2-[(4-methylphenyl)ethynyl]-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 17b

1H-NMR (ppm, CDCl₃, 300 MHz): 1.48 (3H), 1.64 (3H), 2.36 (3H), 2.57 (3H), 2.60-2.80 (3H), 7.08-7.20 (3H), 7.30 (4H), 7.49 (2H), 7.60 (1H), 8.29 (2H), 8.90 (1H).

16a: [α]^(D) ₂₀: +28.4° (CHCl₃, 1.03 g/100 ml; λ=589 nm)

16b: [α]^(D) ₂₀: −28.6° (CHCl₃, 1.01 g/100 ml; λ=589 nm)

rac-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 18

1H-NMR (ppm, CDCl₃, 300 MHz): 1.47 (3H), 1.63 (3H), 2.56 (3H), 2.60-2.78 (3H), 3.80 (3H), 6.81 (2H), 7.13 (1H), 7.25-7.38 (4H), 7.48 (2H), 7.60 (1H), 8.28 (2H), 8.89 (1H).

(+)-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 18a and (−)-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 18b

The racemic mixture which was described in example 18 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 18a and 18b.

18a: [α]^(D) ₂₀: +29.3° (CHCl₃, 1.12 g/100 ml; λ=589 nM)

18b: ([α]^(D) ₂₀: −30.0° (CHCl₃, 1.14 g/100 ml; λ=589 nM)

rac-6-[2-Hydroxy-2-[(4-(N,N-dimethylamino)phenyl)ethynyl]4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 19

1H-NMR (ppm, CDCl₃, 400 MHz): 1.48 (3H), 1.62 (3H), 2.57 (3H), 2.60-2.75 (3H), 2.98 (6H), 6.58 (2H), 7.12 (1H), 7.23-7.38 (4H), 7.48 (2H); 7.57 (1H), 8.28 (2H), 8.90 (1H).

rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluoromethyl phenyl)ethynyl]-pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 20

1H-NMR (ppm, CDCl₃, 400 MHz): 1.48 (3H), 1.63 (3H), 2.57 (3H), 2.64-2.80 (3H), 7.17 (1H), 7.33 (2H), 7.48 (4H), 7.56 (2H), 7.61 (1H), 8.30 (2H), 8.92 (1H).

(+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluormethylphenyl)ethynyl]-pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 20a and (−)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluormethylphenyl)ethynyl]-pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 20b

The racemic mixture which was described in example 20 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 20a and 20b.

20a: [α]^(D) ₂₀: +19.9° (CHCl₃, 1.05 g/100 ml; λ=589 nM)

20b: [α]^(D) ₂₀: −20.4° (CHCl₃, 1.01 g/100 ml; λ=589 nM)

rac-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenyl pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 21

1H-NMR (ppm, CDCl₃, 400 MHz): 1.50 (3H), 1.62 (3H), 2.57 (3H), 2.63-2.82 (3H), 7.18 (1H), 7.35 (2H), 7.48 (4H), 7.55-7.68 (2H), 7.62 (1H), 8.30 (2H), 8.94 (1H).

(+)-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 21a and (−)-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 21b

The racemic mixture which was described in example 21 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 21a and 21b.

21a: [α]D₂₀: +26.6° (CHCl₃, 1.12 g/100 ml; λ=589 nM)

21b: [α]^(D) ₂₀: −26.8° (CHCl₃, 1.02 g/100 ml; λ=589 nM)

rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenylphenyl)ethynyl]pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 22

1H-NMR (ppm, CDCl₃, 400 MHz): 1.50 (3H), 1.68 (3H), 2.58 (3H), 2.64-2.81 (3H), 7.18 (1H), 7.30-7.40 (3H), 7.41-7.61 (11H), 8.30 (2H), 8.92 (1H).

(+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenyl phenyl)ethynyl]pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 22a and (−)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenylphenyl)ethynyl]pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 22b

The racemic mixture which was described in example 22 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 22a and 22b.

22a: [α]^(D) ₂₀: +38.4° (CHCl₃, 1.06 g/100 ml; λ=589 nM)

22b: [α]^(D) ₂₀: −30.60 (CHCl₃, 1.12 g/100 ml; λ=589 nM)

rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(3-trifluoromethylphenyl)ethynyl]-pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 23

1H-NMR (ppm, CDCl₃, 300 MHz): 1.52 (3H), 1.68 (3H), 2.60 (3H), 2.65-2.88 (3H), 7.21 (1H), 7.49 (2H), 7.42-7.70 (7H), 8.34 (2H), 8.96 (1H).

rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluoromethylphenyl)ethynyl]-pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 24

1H-NMR (ppm, CDCl₃, 600 MHz): 1.52 (3H), 1.65 (3H), 2.62 (3H), 2.69 (1H), 2.78 (1H), 2.91 (1H), 7.11 (1H), 7.32 (3H), 7.51 (3H), 7.57 (2H), 7.70 (1H), 8.20 (1H), 8.45 (1H), 8.75 (1H).

(+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluormethylphenyl)ethynyl]-pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 24a and (−)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluormethylphenyl)ethynyl]-pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 24b

The racemic mixture which was described in example 24 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 24a and 24b.

24a: [α]^(D) ₂₀: +21.3° (CHCl₃, 1.00 g/100 ml; λ=589 nM)

24b: [α]^(D) ₂₀: 19.4° (CHCl₃, 1.00 g/100 ml; λ=589 nM)

rac-6-[2-Hydroxy-4-methyl-2-[(4-nitrophenyl)ethynyl]-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 25

1H-NMR (ppm, CDCl₃, 600 MHz): 1.47 (3H), 1.62 (3H), 2.55 (3H), 2.79 (1H), 2.81 (2H), 7.18 (1H), 7.34 (2H), 7.50 (4H), 7.63 (1H), 8.17 (2H), 8.80 (2H), 8.94 (1H).

rac-6-[2-[[4-(1,1-Dimethylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl -4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 26

1H-NMR (ppm, CDCl₃, 300 MHz): 1.32 (9H), 1.51 (3H), 1.68 (3H), 2.62 (3H), 2.65-2.82 (3H), 7.18 (1H), 7.30-7.40 (6H), 7.52 (2H), 7.63 (1H), 8.32 (2H), 8.93 (1H).

rac-6-[2-Hydroxy-4-methyl-2-[(3-methylphenyl)ethynyl]-4-phenyl pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 27

1H-NMR (ppm, CDCl₃, 400 MHz): 1.47 (3H), 1.63 (3H), 2.30 (3H), 2.58 (3H), 2.62-2.80 (3H), 7.12-7.26 (5H), 7.32 (2H), 7.50 (2H), 7.60 (1H), 8.30 (2H), 8.90 (1H).

rac-6-[2-Hydroxy-4-methyl-2-[(2-methylphenyl)ethynyl]-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 28

1H-NMR (ppm, CDCl₃, 300 MHz): 1.47 (3H), 1.65 (3H), 2.38 (3H), 2.58 (3H), 2.62-2.80 (3H), 7.08-7.42 (7H), 7.49 (2H), 7.60 (1H), 8.22-8.36 (2H), 8.90 (1H).

rac-6-[2-(3,3-Dimethylbutynyl)-2-hydroxy-4-methyl-4-phenyl pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 29

1H-NMR (ppm, CDCl₃; 300 MHz): 1.20 (9H), 1.43 (3H), 1.60 (3H), 2.46 (1H), 2.50-2.63 (5H), 7.11 (1H), 7.28 (2H), 7.43 (2H), 7.54 (1H), 8.22 (1H), 8.29 (1H), 8.32 (1H).

The following compound was prepared in analogy to Example 7 from the compound described in Example 13 and 4′-iodoacetophenone:

rac-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 30

1H-NMR (ppm, CDCl₃, 300 MHz): 1.48 (3H), 1.63 (3H), 2.56 (3H), 2.60 (3H), 2.63-2.82 (3H), 7.18 (1H), 7.33 (2H), 7.40-7.56 (4H), 7.62 (1H), 7.90 (2H), 8.30 (2H), 8.93 (1H).

(+)-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 30a and (−)-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 30b

The racemic mixture which was described in example 30 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 30a and 30b.

30a: [α]^(D) ₂₀: +31.3° (CHCl₃, 1.09 g/100 ml; λ=589 nM)

30b: [α]^(D) ₂₀: −28.4° (CHCl₃, 1.09 g/100 ml; λ=589 nM)

The compounds 30 and 31 were prepared in analogy to Example 1 from 6-[3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionylamino]-4-methyl-2,3-benzoxazin-1-one

rac-6-[2-[(2-Fluoro-5-trifluoromethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluoromethylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 31

1H-NMR (ppm, CDCl₃, 400 MHz): 0.90 (1H), 1.00-1.15 (3H), 2.51 (1H), 2.55 (3H), 2.68 (1H), 3.18 (1H), 7.01 (1H), 7.30 (1H), 7.41 (2H), 7.56 (2H), 7.63 (1H), 7.68 (1H), 8.19 (1H), 8.31 (1H), 8.98 (1H).

(+)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluormethylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 31a and (−)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluormethylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin−1-one 31b

The racemic mixture which was described in, example 31 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 31a and 31b.

31a: [α]^(D) ₂₀: +2.3° (CHCl₃, 1.00 g/100 ml; λ=589 nM)

31b: [α]^(D) ₂₀: −1.9° (CHCl₃, 1.00 g/100 ml; λ=589 nM)

rac-6-[2-[(2-Fluoro-5-trifluoromethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3-ynoylamino]-4-methyl-2,3-benzoxazin-1-one 32

1H-NMR (ppm, CDCl₃, 400 MHz): 0.88 (1H), 0.98-1.13 (3H), 2.34 (3H), 2.44 (1H), 2.55 (3H), 2.70 (1H), 3.02 (1H), 7.01 (1H), 7.10 (2H), 7.22 (2H), 7.30 (1H), 7.64 (2H), 8.19 (1H), 8.31 (1H), 8.98 (1H).

(+)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 32a and (−)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin−1-one 32b

The racemic mixture which was described in example 32 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 32a and 32b.

32a: [α]^(D) ₂₀: +8.6° (CHCl₃, 1.00 g/100 ml; λ=589 nM)

32b: [α]D₂₀: −8.7° (CHCl₃, 1.00 g/100 ml; λ=589 nM)

The following compound was prepared in analogy to example 7 from compound which was described in example 14 and 3′-Iodacetophenon:

rac-6-[2-[(3-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 33

1H-NMR (ppm, CDCl₃, 300 MHz): 1.49 (3H), 1.63 (3H), 2.57 (6H), 2.62-2.81 (3H), 7.16 81H), 7.28-7.70 (7H), 7.90-8.00 (2H), 8.30 (2H), 8.94 (1H).

Compounds 34 and 35 were prepared in analogy to example 1 from 6-(4-Methyl-4-phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the according Lithium arylacetylide.

rac-6-[2-[(2,5-Dimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 34

1H-NMR (ppm, CDCl₃, 400 MHz): 1.49 (3H), 1.62 (3H), 2.27 (3H), 2.33 (3H), 2.57 (3H), 2.65-2.78 (3H), 7.03 (2H), 7.13 (2H), 7.30 (2H), 7.50 (2H), 7.61 (1H), 8.22 (1H), 8.30 (1H), 8.89 (1H).

rac-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 35

1H-NMR (ppm, CDCl₃, 400 MHz): 1.47 (3H), 1.64 (3H), 2.18 (3H), 2.21 (3H), 2.30 (3H), 2.56 (3H), 2.65-2.77 (3H), 6.93 (1H), 7.12 (2H), 7.30 (2H), 7.48 (2H), 7.59 (1H), 8.22 (1H), 8.29 (1H), 8.90 (1H).

(+)-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 35a and (−)-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 35b

The racemic mixture which was described in example 35 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 35a and 35b.

35a: [α]^(D) ₂₀: +30.6° (CHCl₃, 0.97 g/100 ml; λ=589 nM)

35b: [α]^(D) ₂₀: −28.0° (CHCl₃, 0.96 g/100 ml; λ=589 nM)

The following compound was prepared in analogy to example 9 from 3-Phenyl-1-propine, nBuLi and 6-(4-Methyl-4-phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin -1-one:

rac-6-{2-(2-phenyl)-2-methylpropyl]-2-hydroxy-5-phenylpent-3-inoylamino}-4-methyl-2,3-benzoxazin-1-one 36

1H-NMR (ppm, CDCl₃, 400 MHz): 1.42 (3H), 1.53 (3H), 2.55-2.70 (6H), 3.58 (2H), 7.11 (1H), 7.20-7.35 (7H), 7.41 (2H), 7.48 (1H), 8.20 (1H), 8.28 (1H), 8.80 (1H).

Compounds 37 and 38 were prepared in analogy to example 1 from 6-(4-Methyl-4-(2-chlor-6-fluorphenyl)-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the according Lithium arylacetylide.

rac-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenylethinyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 37

1H-NMR (ppm, CDCl₃, 300 MHz): 1.73 (3H), 1.82 (3H), 2.33 (3H), 2.57 (3H), 2.88-3.02 (3H), 6.75-6.96 (2H), 7.01 (1H), 7.09 (2H), 7.27 (2H), 7.60 (1H), 8.22-8.35 (2H), 8.96 (1H).

(+)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenylethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 37a and (−)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenylethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 37b

The racemic mixture which was described in example 37 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 37a and 37b.

37a: [α]^(D) ₂₀: +21.5° (CHCl₃, 100 g/100 ml; λ=589 nM)

37b: [α]^(D) ₂₀: −21.0° (CHCl₃, 1.04 g/100 ml; λ=589 nM)

rac-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-(trifluormethyl)phenylethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 38

1H-NMR (ppm, CDCl₃, 400 MHz): 1.60 (3H), 1.93 (3H), 2.36 (1H), 2.56-2.72 (5H), 7.04 (1H), 7.14 (2H), 7.45 (2H), 7.53 (2H), 7.80 (1H), 8.35-8.45 (2H), 8.90 (1H).

(+)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-(trifluormethyl)phenylethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 38a and (−)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-(trifluormethyl)phenylethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 38b

The racemic mixture which was described in example 38 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers-38a and 38b.

38a: [α]^(D) ₂₀: +143.2° (CHCl₃, 1.05 g/100 ml; λ=589 nM)

38b: [α]20: 137.8° (CHCl₃, 1.12 g/100 ml; λ=589 nM)

Compounds 39 and 40 were prepared in analogy to example 1 from 6-(4-Methyl-4-(2-chlorphenyl)-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the according Lithium arylacetylide.

rac-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 39

1H-NMR (ppm, CDCl₃, 400 MHz): 0.84 (1H), 1.00 (1H), 1.08-1.22 (2H), 2.36 (3H), 2.53 (3H), 2.90 (1H), 7.03-7.18 (4H), 7.23-7.38 (3H), 7.50 (1H), 7.60 (1H), 8.22 (1H), 8.29 (1H), 8.91 (1H).

(+)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 39a and (−)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 39b

The racemic mixture which was described in example 39 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 39a and 39b.

39a: [α]^(D) ₂₀: +30.8° (CHCl₃, 1.00 g/100 ml; λ=589 nM)

39b: [α]^(D) ₂₀: −28.3° (CHCl₃, 1.00 g/100 ml; λ=589 nM)

rac-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluormethylphenyl)but -3-inoylamino]-4-methyl-2,3-benzoxazin−1-one 40

1H-NMR (ppm, CDCl₃, 300 MHz): 0.91 (1H), 1.02 (1H), 1.08-1.25 (2H), 2.53 (3H), 3.00 (1H), 7.02-7.18 (2H), 7.28 (1H), 7.42-7.54 (3H), 7.55-7.67 (3H), 8.22 (1H), 8.32 (1H), 8.91 (1H).

(+)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluormethylphenyl)but -3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 40a and (−)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluormethylphenyl)but -3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 40b

The racemic mixture which was described in example 40 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 40a and 40b.

40a: [α]^(D) ₂₀: +20.9° (CHCl₃, 1.06 g/100 ml; λ=589 nM)

40b: [α]^(D) ₂₀: −20.6° (CHCl₃, 1.05 g/100 ml; λ=589 nM)

rac-6-[2-[[3-(1-Hydroxy-1-methylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 41

59 μl of 3 molar solution of Methylmagnesium chloride was diluted with 1 ml of pure Tetrahydrofurane. The solution was cooled to −70° C. and a solution of 30 mg of the compound which was described in example 33 in 0,5 ml of pure Tetrahydrofurane was added. After stirring for 2,5 hours at −70° C. the mixture was given to a saturated solution of ammonium chloride. After extracting the mixture with Ethyl acetate the combined organic phases were washed with saturated sodium chloride and dried over sodium sulphate. After column chromatography 16 mg of the product was obtained.

¹H-NMR (ppm, CDCl₃, 400 MHz): 1.46 (3H), 1.53 (6H), 1.62 (3H), 1.80 (1H), 2.55 (3H), 2.65-2.90 (3H), 7.12 (1H), 7.30 (3H), 7.40-7.52 (3H), 7.53 (1H), 7.60 (1H), 8.27 (2H), 8.95 (1H).

The following compound was prepared in analogy to example 7 from the compound which was described in example 14 and 4-Iodobenzylalcohol:

rac-6-[2-[[4-(Hydroxymethyl)phenyl]ethynyl]-2-hydroxy-4-methyl -4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 42

1H-NMR (ppm, CDCl₃, 300 MHz): 1.47 (3H), 1.60 (3H), 1.80 (1H), 2.57 (3H), 2.62-2.83 (3H), 4.68 (2H), 7.13 (1H), 7.25-7.43 (6H), 7.48 (2H), 7.59 (1H), 8.25-8.32 (2H), 8.91 (1H).

The following compound was prepared in analogy to example 7 from the compound which was described in example 14 and 4-Iodobenzylalcohol:

rac-6-[2-[[3-(Hydroxytnethyl)phenyl]ethinyl]-2-hydroxy-4-methyl -4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 43

1H-NMR (ppm, CDCl₃, 400 MHz): 1.48 (3H), 1.62 (3H), 1.79 (1H), 2.57 (3H), 2.62-2.80 (3H), 4.68 (2H), 7.15 (1H), 7.25-7.39 (5H), 7.40 (1H), 7.49 (2H), 7.60 (1H), 8.29 (2H), 8.91 (1H).

The following compound was prepared in analogy to example 41 from the compound which was described in example 30 and a solution of Methyl magnesium chloride:

rac-6-[2-[[4-(1-Hydroxy-1-methylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl -4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 44

1H-NMR (ppm, CDCl₃, 400 MHz): 1.47 (3H), 1.55 (6H), 1.62 (3H), 1.70 (1H), 2.55 (3H), 2.60-2.80 (3H), 7.14 (1H), 7.28-7.40 (4H), 7.41 (2H), 7.48 (2H), 7.60 (1H), 8.25-8.32 (2H), 8.90 (1H).

The entire disclosures of all applications, patents and publications, cited-herein and of corresponding German application No. 102005030292.0-44, filed Jun. 24, 2005 and U.S. Provisional Application Ser. No. 60/693,403 filed Jun. 24, 2005, are incorporated by reference herein.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. 

1. Compounds of the general formula I

R¹ and R² are independently of one another a hydrogen atom, a linear or nonlinear, branched or unbranched C₁-C₅-alkyl group, further forming together with the C atom of the chain a ring having a total of 3-7 members, R³ is a radical C≡C—R^(a), where R^(a) is a hydrogen or a C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl, heterocycloalkyl optionally substituted one or more times, identically or differently, by K, or an aryl or heteroaryl optionally substituted one or more times, identically or differently by L, K is a cyano, halogen, hydroxy, nitro, —C(O)R^(b), CO₂R^(b), —O—R^(b), —S—R^(b), SO₂NR^(c)R^(d), —C(O)—NR^(c)R^(d), —OC(O)—NR^(c)R^(d), —C═NOR^(b)—NR^(c)R^(d) or C₃-C₁₀-cycloalkyl, heterocycloalkyl optionally substituted one or more times, identically or differently, by M, or aryl or heteroaryl optionally substituted one or more times by L, L is C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₁-C₆-perfluoroalkyl, C₁-C₆-perfluoroalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkoxy, (CH₂)_(p)—C₃-C₁₀-cycloalkyl, (CH₂)_(p)-heterocycloalkyl, (CH₂)_(p)CN, (CH₂)_(p)Hal, (CH₂)_(p)NO₂, (CH₂)_(p)—C₆-C₁₂-aryl, (CH₂)_(p)-heteroaryl, —(CH₂)_(p)PO₃(R^(b))₂, —(CH₂)_(p)NR^(c)R^(d), —(CH₂)_(p)NR^(e)COR^(b), —(CH₂)_(p)NR^(e)CSR^(b), —(CH₂)_(p)NR^(e)S(O)R^(b), —(CH₂)_(p)NR^(e)S(O)₂R^(b), —(CH₂)_(p)NR^(e)CONR^(c)R^(d), —(CH₂)_(p)NR^(e)COOR^(b), —(CH₂)_(p)NR^(e)C(NH)NR^(c)R^(d), —(CH₂)_(p)NR^(e)CSNR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)NR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)₂NR^(c)R^(d), —(CH₂)_(p)COR^(b), —(CH₂)_(p)CSR^(b), —(CH₂)_(p)S(O)R^(b), —(CH₂)_(p)S(O)(NH)R^(b), —(CH₂)_(p)S(O)₂R^(b), —(CH₂)_(p)S(O)₂NR^(c)R^(d), —(CH₂)_(p)SO₂OR^(b), —(CH₂)_(p)CO₂R^(b), —(CH₂)_(p)CONR^(c)R^(d), —(CH₂)_(p)CSNR^(c)R^(d), —(CH₂)_(p)OR^(b), —(CH₂)_(p)SR^(b), —(CH₂)_(p)CR^(b)(OH)—R^(e), —(CH₂)_(p)—C═NOR^(b), —O—(CH₂), —O—, —O—(CH₂), —CH₂—, —O—CH═CH— or —(CH₂)_(n+2)—, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring carbon atoms, M is C₁-C₆-alkyl or a group —COR^(b), CO₂R^(b), —O—R^(b), or —NR^(c)R^(d), where R^(b) is a hydrogen or a C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl, C₆-C₁₂-aryl or C₁-C₃-perfluoroalkyl and R^(c) and R^(d) are independently of one another a hydrogen, C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl, C₆-C₁₂-aryl, C(O)R^(b) or a hydroxy group, where if R^(c) is a hydroxy group, then R^(d) can only be a hydrogen, a C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl and vice versa, and R^(e) is a hydrogen, C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl, and p can be a number from 0-6, or R³ is a radical C═C—R^(g)R^(h), where R^(g) and R^(h) are independently of one another a hydrogen or a C₁-C₈-alkyl, C₂-C₈-alkenyl or C₂-C₈-alkynyl optionally substituted one or more times, identically or differently, by X, in which X is a cyano, halogen, hydroxy, nitro, —C(O)R^(b), CO₂R^(b), —O—R^(b), —C(O)—NR^(c)R^(d), —NR^(c)R^(d) with the meanings already mentioned before for R^(b), R^(c) and R^(d), and R⁴ is a hydrogen atom, a methyl or an ethyl group or a partly or completely fluorinated C₁-C₃-alkyl group, A is a mono- or bicyclic carbocyclic or heterocyclic aromatic ring which may optionally be substituted one or more times by C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₁-C₆-perfluoroalkyl, C₁-C₆-perfluoroalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy, (CH₂)_(p)—C₃-C₁₀-cycloalkyl, (CH₂)_(p)-heterocycloalkyl, (CH₂)_(p)CN, (CH₂)_(p)Hal, (CH₂)_(p)NO₂, (CH₂)_(p)—C₆-C₁₂-aryl, (CH₂)_(p)-heteroaryl, —(CH₂)_(p)PO₃(R^(b))₂, —(CH₂)_(p)NR^(c)R^(d), —(CH₂)_(p)NR^(e)COR^(b), —(CH₂)_(p)NR^(e)CSR^(b), —(CH₂)_(p)NR^(e)S(O)R^(b), —(CH₂) NR^(e)S(O)₂R^(b), —(CH₂)_(p)NR^(e)CONR^(c)R^(d), —(CH₂)_(p)NR^(e)COOR^(b), —(CH₂)_(p)NR^(e)C(NH)NR^(c)R^(d), —(CH₂)_(p)NR^(e)CSNR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)NR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)₂NR^(c)R^(d), (CH₂)_(p)COR^(b), —(CH₂)_(p)CSR^(b), —(CH₂)_(p) S(O)R^(b), —(CH₂)_(p)S(O)(NH)R^(b), —(CH₂)_(p)S(O)₂R^(b), —(CH₂)_(p)S(O)₂NR^(c)R^(d), —(CH₂)_(p)SO₂OR^(b), —(CH₂)_(p)CO₂R^(b), —(CH₂)_(p)CONR^(c)R^(d), —(CH₂)_(p)CSNR^(c)R^(d), —(CH₂)_(p)OR^(b), —(CH₂)_(p)SR^(b), —(CH₂)_(p)CR^(b)(OH)—R^(d), —(CH₂)_(p)—C═NOR^(b), —O—(CH₂), —O—, —O—(CH₂), —CH₂—, —O—CH═CH— or —(CH₂)_(n+2)—, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring carbon atoms, or A is a radical —CO₂R^(b), C(O)NR^(c)R^(d), COR^(b), or A is an alkenyl group —CR⁵═CR⁶R⁷, where R⁵, R⁶ and R⁷ are identical or different and are independently of one another hydrogen atoms, halogen atoms, aryl radicals or an unsubstituted or partly or completely fluorinated C₁-C₅-alkyl group, or A is an alkynyl group —C≡CR⁵, with the meaning stated above for R⁵, and B is a carbonyl or a CH₂ group and their pharmaceutically acceptable salts.
 2. Compounds according to claim 1, in which R¹ and R² are preferably a hydrogen atom, a methyl or ethyl group.
 3. Compounds according to claim 1, in which R¹ and R² preferably form together with the C atom of the chain a ring having a total of 3-7 members.
 4. Compounds according to claim 1, in which R³ is preferably alkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, cycloalkylalkynyl, heterocycloalkylalkynyl.
 5. Compounds according to claim 1, in which R³ is preferably a vinyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, hydroxypropynyl, hydroxybutynyl, 3-hydroxy-3-methylbutynyl, hydroxypentynyl, carboxypropynyl, t-butylcarboxypropynyl, phenylethynyl, (hydroxyphenyl)ethynyl, (methoxyphenyl)ethynyl, (dimethylaminophenyl)ethynyl, (methylphenyl)ethynyl, (cyanophenyl)ethynyl, (trifluoromethyl)ethynyl, (diphenyl)ethynyl, (nitrophenyl)ethynyl, (tert-butylphenyl)ethynyl, (acetylphenyl)ethynyl, (acetoxyphenyl)ethynyl, (carboxyphenyl)ethynyl or a benzylethynyl group.
 6. Compounds according to claim 1, in which A is preferably an aromatic ring.
 7. Compounds according to claim 1, in which A is preferably a phenyl or naphthyl radical.
 8. Compounds according to claim 7, in which A is preferably an unsubstituted or optionally mono- or polysubstituted phenyl radical.
 9. Compounds according to claim 8, where the phenyl radical is preferably substituted by one or two halogen atoms or one trifluoromethyl group.
 10. Compounds according to claim 9, in which the halogen atoms are preferably chlorine and/or fluorine.
 11. Compounds according to claim 1, in which A is preferably a phenyl ring substituted by —O—(CH₂)_(n)—O— or —O—(CH₂)_(n)—CH₂—, where the respectively directly adjacent ring carbon atoms are linked.
 12. Compounds according to claim 1, in which R⁴ is a hydrogen atom, a methyl or a trifluoromethyl radical.
 13. Compounds according to claim 1, namely Racemic or No. enantiomer R3

  1   2   3 rac −+

  4   5   6 rac +−

  7   8   9 rac +−

 10  11  12 rac +−

 13  14  15 rac +−

 16  17  18 rac +−

 19  20  21 rac +−

 22  23  24 rac +−

 25  26  27 rac +−

 28  29  30 rac +−

 31  32  33 rac +−

 34  35  36 rac +−

 37  38  39 rac +−

 40  41  42 rac +−

 43  44  45 rac +−

 46  47  48 rac +−

 49  50  51 rac +−

 52  53  54 rac −+

 55  56  57 rac +−

 58  59  60 rac +−

 61  62  63 rac +−

 64  65  66 rac +−

 67  68  69 rac +−

 70  71  72 rac +−

 73  74  75 rac +−

 76  77  78 rac +−

 79  80  81 rac +−

 82  83  84 rac +−

 85  86  87 rac +−

 88  89  90 rac +−

 91  92  93 rac +−

 94  95  96 rac +−

 97  98  99 rac +−

 100  191  102 rac +−

 103  104  105 rac +−

 106  107  108 rac −+

 109  110  111 rac +−

 112  113  114 rac +−

 115  116  117 rac +−

 118  119  120 rac +−

 121  122  123 rac +−

 124  125  126 rac +−

 127  128  129 rac +−

 130  131  132 rac +−

 133  134  135 rac +−

 136  137  138 rac +−

 139  140  141 rac +−

 142  143  144 rac +−

 145  146  147 rac +−

 148  149  150 rac +−

 151  152  153 rac +−

 154  155  156 rac +−

 157  158  159 rac +−

 160  161  162 rac +−

 163  164  165 rac +−

 166  167  168 rac +−

 169  170  171 rac −+

 172  173  174 rac +−

 175  176  177 rac +−

 178  179  180 rac +−

 181  182  183 rac +−

 184  185  186 rac +−

 187  188  189 rac +−

 190  191  192 rac +−

 193  194  195 rac +−

 196  197  198 rac +−

 199  200  201 rac +−

 202  203  204 rac +−

 205  206  207 rac +−

 208  209  210 rac +−

 211  212  213 rac +−

 214  215  216 rac +−

 217  218  219 rac +−

 220  221  222 rac +−

 223  224  225 rac +−

 226  227  228 rac +−

 229  230  231 rac +−

 232  233  234 rac −+

 235  236  237 rac +−

 238  239  240 rac +−

 241  242  243 rac +−

 244  245  246 rac +−

 247  248  249 rac +−

 250  251  252 rac +−

 253  254  255 rac +−

 256  257  258 rac +−

 259  260  261 rac +−

 262  263  264 rac +−

 265  266  267 rac +−

 268  269  270 rac +−

 271  272  273 rac +−

 274  275  276 rac +−

 277  278  279 rac +−

 280  281  282 rac +−

 283  284  285 rac +−

 286  287  288 rac +−

 289  290  291 rac +−

 292  293  294 rac +−

 295  296  297 rac −+

 298  299  300 rac +−

 301  302  303 rac +−

 304  305  306 rac +−

 307  308  309 rac +−

 310  311  312 rac +−

 313  314  315 rac +−

 316  317  317 rac +−

 319  320  321 rac +−

 322  323  324 rac +−

 325  326  327 rac +−

 328  329  330 rac +−

 331  332  333 rac +−

 334  335  336 rac +−

 337  338  339 rac +−

 340  341  342 rac +−

 343  344  345 rac +−

 346  347  348 rac +−

 349  350  351 rac +−

 352  353  354 rac +−

 355  356  357 rac +−

 358  359  360 rac −+

 361  362  363 rac +−

 364  365  366 rac +−

 367  368  369 rac +−

 370  371  372 rac +−

 373  374  375 rac +−

 376  377  378 rac +−

 379  380  381 rac +−

 382  383  384 rac +−

 385  386  387 rac +−

 388  389  390 rac +−

 391  392  393 rac +−

 394  395  396 rac +−

 397  398  399 rac +−

 400  401  402 rac +−

 403  404  405 rac +−

 406  407  408 rac +−

 409  410  411 rac +−

 412  413  414 rac +−

 415  416  417 rac +−

 418  419  420 rac +−

 421  422  423 rac −+

 424  425  426 rac +−

 427  428  429 rac +−

 430  431  432 rac +−

 433  434  435 rac +−

 436  437  438 rac +−

 439  440  441 rac +−

 442  443  444 rac +−

 445  446  447 rac +−

 448  449  450 rac +−

 451  452  453 rac +−

 454  455  456 rac +−

 457  458  459 rac +−

 460  461  462 rac +−

 463  464  465 rac +−

 466  467  468 rac +−

 469  470  471 rac +−

 472  473  474 rac +−

 475  476  477 rac +−

 478  479  480 rac +−

 481  482  483 rac +−

 484  485  486 rac −+

 487  488  489 rac +−

 490  491  492 rac +−

 493  494  495 rac +−

 496  497  498 rac +−

 499  500  501 rac +−

 502  503  504 rac +−

 505  506  507 rac +−

 508  509  510 rac +−

 511  512  513 rac +−

 514  515  516 rac +−

 517  518  519 rac +−

 520  521  522 rac +−

 523  524  525 rac +−

 526  527  528 rac +−

 529  530  531 rac +−

 532  533  534 rac +−

 535  536  537 rac +−

 538  539  540 rac +−

 541  542  543 rac +−

 544  545  546 rac +−

 547  548  549 rac −+

 550  551  552 rac +−

 553  554  555 rac +−

 556  557  558 rac +−

 559  560  561 rac +−

 562  563  564 rac +−

 565  566  567 rac +−

 568  569  570 rac +−

 571  572  573 rac +−

 574  575  576 rac +−

 577  578  579 rac +−

 580  581  582 rac +−

 583  584  585 rac +−

 586  587  588 rac +−

 589  590  591 rac +−

 592  593  594 rac +−

 595  596  597 rac +−

 598  599  600 rac +−

 601  602  603 rac +−

 604  605  606 rac +−

 607  608  609 rac +−

 610  611  612 rac −+

 613  614  615 rac +−

 616  617  618 rac +−

 619  620  621 rac +−

 622  623  624 rac +−

 625  626  627 rac +−

 628  629  630 rac +−

 631  632  633 rac +−

 634  635  636 rac +−

 637  638  639 rac +−

 640  641  642 rac +−

 643  644  645 rac +−

 646  647  648 rac +−

 649  650  651 rac +−

 652  653  654 rac +−

 655  656  657 rac +−

 658  659  660 rac +−

 661  662  663 rac +−

 664  665  666 rac +−

 667  668  669 rac +−

 670  671  672 rac +−

 673  674  675 rac −+

 676  677  678 rac +−

 679  680  681 rac +−

 682  683  684 rac +−

 685  686  687 rac +−

 688  689  690 rac +−

 691  692  693 rac +−

 694  695  696 rac +−

 697  698  699 rac +−

 700  701  702 rac +−

 703  704  705 rac +−

 706  707  708 rac +−

 709  710  711 rac +−

 712  713  714 rac +−

 715  716  717 rac +−

 718  719  720 rac +−

 721  722  723 rac +−

 724  725  726 rac +−

 727  728  729 rac +−

 730  731  732 rac +−

 733  734  735 rac +−

 736  737  738 rac −+

 739  740  741 rac +−

 742  743  744 rac +−

 745  746  747 rac +−

 748  749  750 rac +−

 751  752  753 rac +−

 754  755  756 rac +−

 757  758  759 rac +−

 760  761  762 rac +−

 763  764  765 rac +−

 766  767  768 rac +−

 769  770  771 rac +−

 772  773  774 rac +−

 775  776  777 rac +−

 778  779  780 rac +−

 781  782  783 rac +−

 784  785  786 rac +−

 787  788  789 rac +−

 790  791  792 rac +−

 793  794  795 rac +−

 796  797  798 rac +−

 799  800  801 rac −+

 802  803  804 rac +−

 805  806  807 rac +−

 808  809  810 rac +−

 811  812  813 rac +−

 814  815  816 rac +−

 817  818  819 rac +−

 820  821  822 rac +−

 823  824  825 rac +−

 826  827  828 rac +−

 829  830  831 rac +−

 832  833  834 rac +−

 835  836  837 rac +−

 838  839  840 rac +−

 841  842  843 rac +−

 844  845  846 rac +−

 847  848  849 rac +−

 850  851  852 rac +−

 853  854  855 rac +−

 856  857  858 rac +−

 859  860  861 rac +−

 862  863  864 rac −+

 865  866  867 rac +−

 868  869  870 rac +−

 871  872  873 rac +−

 874  875  876 rac +−

 877  878  879 rac +−

 880  881  882 rac +−

 883  884  885 rac +−

 886  887  888 rac +−

 889  890  891 rac +−

 892  893  894 rac +−

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14. Pharmaceutical composition comprising at least one compound of the general formula I according to claim 1 and, where appropriate, at least one further active ingredient together with pharmaceutically suitable excipients and/or carriers.
 15. Pharmaceutical composition according to claim 14, where the further active ingredient is a SERM (selective estrogen receptor modulator), an aromatase inhibitor, an antiestrogen or a prostaglandin.
 16. Pharmaceutical composition according to claim 14, where the active ingredient may be tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulphinyl]pentyloxy}phenyl) -6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol, ICI 182 780 (7alpha-[9-(4,4,5,5-pentafluoropentylsulphinyl)nonyl]estra-1,3,5(10)-triene-3,17beta-diol), 11beta-fluoro-7alpha-[5-(methyl {3-[(4,4,5,5,5-pentafluoropentyl)sulphanyl]propyl}amino)pentyl]estra-1,3,5(10)-triene -3,17beta-diol, 11beta-fluoro-7alpha-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol, 11beta-fluoro-17alpha-methyl -7alpha-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}estra-1,3,5(10)-triene -3,17beta-diol, clomifen, raloxifen, fadrozole, formestane, letrozole, anastrozole or atamestane.
 17. Use of compounds according to claim 1 for producing a medicament.
 18. Use of compounds according to claim 17 for producing a medicament for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea.
 19. Use of compounds according to claim 17 for producing a medicament for the therapy and prophylaxis of hormone-dependent tumours.
 20. Use of compounds according to claim 17 for producing a medicament for the therapy and prophylaxis of breast carcinomas.
 21. Use of compounds according to claim 17 for producing a medicament for the therapy and prophylaxis of endometrial carcinoma.
 22. Use of compounds according to claim 17 for producing a medicament for the therapy and prophylaxis of ovarian carcinomas.
 23. Use of compounds according to claim 17 for producing a medicament for the therapy and prophylaxis of prostate carcinomas.
 24. Use of compounds according to claim 17 for producing a medicament for female hormone replacement therapy.
 25. Use of compounds according to claim 17 for female fertility control.
 26. Process for the selective addition of lithium alkynyl and magnesium haloalkynyl compounds onto a keto amide. 